Special Report on Assays, Test Methods, and Comparability The CMC Strategy Forum Series, Part 4, The Roles of Bioactivity Assays in Lot Release and Stability Testing

A January 2007 CMC Strategy Forum on the roles of bioactivity assays in lot release and stability testing was held in Washington, DC (1). Its purpose was to promote an understanding of the design and utility of bioassays throughout product development and to delineate the conditions under which surrogate assays could be used to determine product potency. Topics of discussion included appropriate assay selection at each stage of product development, the potential use of binding assays for potency testing, and the conditions under which multiple surrogate assays might be needed. A second forum in Paris (April 2008) followed up and expanded discussion on these same topics.

Case studies were presented on the role of potency assays in correlating product biological activity to structure and mechanism of action (MoA), development and use of surrogate assays for monoclonal antibody (MAb) testing, and replacement of bioassays with binding or physicochemical assays for complex biological products. Perspectives were provided on the necessary characteristics of a reliable biological assay and the required level of correlation between the bioassay and surrogate assays. Open forums addressed the following questions:

  • How is a potency assay defined and developed throughout the course of a product’s life cycle?

  • What characterization studies should be done to show that a surrogate to biological activity is valid?

  • Under what circumstances might more than one surrogate assay be needed for potency testing?

  • What role might physicochemical assays have in lot release and stability testing, given that they are generally less variable and more sensitive to change?

Those and other relevant issues were discussed at both forums. The Washington, DC forum consisted of two sessions; the Paris forum was a single session. Each session included three presentations followed by an interactive, moderated discussion with questions and comments from the audience. Although this review includes topics and opinions presented at both forums, the format follows that of the first meeting because the two meetings featured the same speakers and similar panel discussions.

Two Sessions
Morning Session: Chana Fuchs (FDA/CDER) discussed the role of potency assays in reflecting biological activity, MoA, and structural attributes of a product. Denise Gavin (FDA/CBER) presented perspectives on potency measurements for complex biologics. Hélène Gazzano-Santoro (Genentech) outlined an industry perspective on method selection, design, and validation, as well as considerations for the use of a surrogate binding assay for the determination of biological activity. These three presenters then participated in a panel discussion moderated by Anthony Mire-Sluis (Amgen).

Afternoon Session: Elizabeth Shores (FDA/CDER) discussed necessary attributes of a potency assay, the relevance of various methodologies to clinical activity, and described case studies using enzyme, binding, and physicochemical assays for potency testing. Robert Strouse (MedImmune) focused on the use of binding assays for high-throughput MAb screening during drug development. Bhavin Parekh (Eli Lilly) outlined drivers and considerations for using physicochemical assays in lot-release potency testing. These three presenters then participated in a panel discussion moderated by Mark Schenerman (MedImmune).

1 Rieder N, et al. Binding Assays and Bioassays: What Are Their Roles in Lot Release and Stability Testing? BioProcess Int. 8(6) 2010.

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